1. Field of the Invention
The invention relates to a genus of benzoxazole carboxamides that are useful in treating chemotherapy-induced nausea and vomiting (CINV) and in treating diarrhea-predominant Irritable Bowel Syndrome (IBS-D).
2. Background
Nausea and vomiting caused by chemotherapy remain among the most distressing side effects for patients undergoing treatment for cancer. Depending upon the chemotherapy agents or regimens given, up to 90% of patients may suffer from some form of chemotherapy-induced nausea and vomiting (CINV). Symptoms from CINV can be severely debilitating and often result in patients refusing further courses of chemotherapy, with obviously unfavorable consequences as regards progression of the cancer. Furthermore, CINV is burdensome on the medical system, consuming time from the healthcare staff, who could otherwise attend to other patients or medical issues.
CINV is divided into two main categories: acute CINV and delayed CINV. Acute CINV occurs within the first 24 hours of treatment; delayed CINV occurs from 24 hours to 120 hours following treatment. Delayed CINV remains a highly under treated side effect in patients undergoing chemotherapy, as healthcare providers tend to underestimate the number of patients who suffer from delayed CINV. Furthermore, delayed CINV greatly impairs patients' ability to provide care to themselves once they have been discharged.
Compounds that inhibit central receptors are currently the most effective anti-emetics; they constitute the single greatest advance in the management of nausea and vomiting in patients with cancer. Blocking the 5-HT3 signal in the CNS appears to prevent acute emesis. All approved 5-HT3 inhibitors, except palonosetron (ALOXI™), are approved to prevent acute CINV. Palonosetron, which must be given intravenously, is the only 5-HT3 inhibitor currently approved for the prevention of delayed CINV. This appears to be due to its long serum half-life. Therefore persons of skill in the art accept that 5-HT3 inhibitors that have long serum half-lives will be effective therapeutic agents for both acute and delayed CINV; those that have short will be useful to treat acute CINV. In addition, the combination of palonosetron, a 5-HT3 inhibitor, and aprepitant (EMEND®), a neurokinin antagonist, has been shown to be highly effective in preventing both acute and delayed CINV following a variety of moderately to highly emetogenic chemotherapy regimens in clinical trials. A large number of other 5-HT3 inhibitors of the “setron” class have been described in clinical and preclinical use for CINV [see review article by Israili, Curr. Med. Chem. CNS Agents 1 171-199 (2001), which is incorporated herein by reference].
Irritable Bowel Syndrome (IBS) generally occurs in two types: diarrhea predominant (IBS-D) and constipation predominant (IBS-C). Diarrhea predominant Irritable Bowel Syndrome is a debilitating, though seldom fatal, disease. The typical sufferer of IBS-D exhibits primary symptoms including multiple and daily explosive diarrhea attacks and severe daily abdominal cramps. The most common secondary side effects include panic attacks, depression, withdrawal from social and family activities and malnutrition.
At present, compounds that inhibit peripheral 5-HT3 receptors are the only effective treatment for IBS-D. The only drug currently approved for IBS-D is alosetron, which was introduced by Glaxo, withdrawn from the clinical trial by the FDA because it caused ischemic colitis, then reinstated by the FDA because the demand was so great for some treatment for IBS-D. In 2002, the US Food and Drug Administration approved alosetron hydrochloride (LOTRONEX®) tablets under restricted conditions for patients in whom the medical benefits outweigh the risks. The restrictions on the approval reflect the serious gastrointestinal adverse events that have been reported with the use of alosetron. A second peripheral 5-HT3 inhibitor, cilanestron, was in clinical trials. Clearly there is a need for improved therapy for both CINV and IBS-D.